The identification of mucosal immune responses induced by invasion of the mucosae by HIV/SIV is essential to identifying responses critical to protection against sexual transmission. The best target for these studies are those individuals who have been mucosally exposed to virus but do not become persistently infected. To this end, we have characterized the immune responses present in the lamina propria (LP) and epithelium of the jejunum, the mesenteric lymph nodes and peripheral blood of 11 rhesus monkeys following colonic exposure to (2) SIV molecular clones (4 SIVmac 239 and 7 SIV/17E-Fr ). Four of the infected monkeys had a strong SIV env-specific, MHC class I restricted CTL response in the LP; whereas only one animal had SIV env-specific IgA-producing B cells in the LP. Three or 6 months post-exposure, these 11 animals and 4 naive controls were challenged intracolonically with a high dose of the heterologous primary isolate, SIV/DeltaB670. All four monkeys with strong SIV env-specific MHC Class I restricted CTL in the LP were protected; whereas, none of the remaining 7 monkeys without CTL in the LP or the naive controls were protected. These data provide the first direct evidence that mucosal infection can induce SIV-specific immunity that remains localized to the gut-associated tissues. Furthermore, there was a strong correlation between SIV env-specific, MHC-restricted CTL in the LP and protection against mucosal challenge with a heterologous primary isolate. We also have begun a longitudinal study using 6 SIV/17E-Fr and 6 SIV/DeltaB670 animals inoculated rectally rather than colonically. Assays were conducted at 1, 2, 3, 4 and 8 wks post inoculation for CTL in peripheral blood. Surgeries were performed at 1, 3, and 8 wks to assay for CTL in the jejunal LP. It would seem that strong env-specific CTL responses occur at different time points in the PBMC and LP among 4 of the 6 SIV/17E-Fr inoculated animals. The induction of CTL is less obvious in the highly pathogenic SIV/DeltaB670 inoculated animals. These animals